The treatment of bacterial infections continues to be an important endeavor of pharmaceutical research and development. The specter of bacterial resistance to currently available antibiotics is ever-present, and accordingly, new and improved compounds, pharmaceutical formulations, treatment methods, and treatment protocols are needed. In addition, bacterial infections present themselves in a wide range of tissues, and in many cases, those tissues pose particular challenges for successful treatment. For example, new treatments of bacterial infections of the respiratory system, including acute and chronic pulmonary and endobronchial infections, are needed.
Many antibiotics do not achieve sufficiently high lung concentrations to be effectively used in the treatment and/or prophylaxis of acute and chronic pulmonary and endobronchial diseases. For example, aminoglycoside penetration into the bronchial secretions has been reported to be poor, at approximately only about 12% of the peak serum concentration (Rev. Infect. Dis., 3:67 (1981)). In addition, it has been reported that sputum itself is inhibitory to the bioactivity of aminoglycosides because of its high ionic strength and the presence of divalent cations (Advances in Pediatric Infections Diseases, 8:53 (1993)). Sputum also contains mucin glycoproteins and DNA, which bind aminoglycosides. It has also been reported that to overcome the inhibitory activity, the concentration of aminoglycosides in the sputum would need to be increased to about ten times the minimum inhibitory concentration of the particular target pathogen, such as Pseudomonas aeruginosa isolates (J. Infect. Dis., 148:1069 (1983)).
It has also been reported that it is particularly difficult to treat cystic fibrosis (CF), a common genetic disease that is characterized by the inflammation and progressive destruction of lung tissue. The debilitation of the lungs in CF patients is associated with accumulation of purulent sputum produced as a result of chronic endobronchial infections caused by pathogenic bacteria, such as H. influenzae, Staphylococcus aureaus, and Pseudomonas aeruginosa, and the like. Nearly all individuals suffering from CF eventually die of respiratory failure.
Because certain antibiotics, like aminoglycosides, penetrate poorly into the sputum, to achieve therapeutic concentrations in sputum, high dose parenteral administration is required. Such dosing regimens increase the risk of systemic toxicity including ototoxicity and nephrotoxicity because the serum contains high aminoglycoside concentrations. Intravenous therapy may also increase hardship on the patient, and require hospitalization, which increases treatment costs and exposes the patient to potential other infections. It is appreciated that during infection, the bacteria may predominantly reside in the smaller airways, such as the terminal and respiratory bronchioles, and that the bacteria may predominantly colonize in the larger airways. It has also been reported that when azithromycin is administered by inhalation and other intrabronchial routes, the half-life in the pharynx and lungs is undesirably long, leading to a higher potential for resistance.
Tobramycin inhalation solution is currently the only aerosol antibiotic approved for use for the treatment of bacterial infections in patients with CF. It has been reported that the aerosol administration of tobramycin reduces the potential for systemic toxicity. However, it has also been reported that long term use has been associated with multiple-antibiotic-resistant P. aeruginosa strains. Thus, there is a need for the development of different treatments, including classes of aerosol antibiotics for the treatment, of chronic lung infections in patients with CF.
It has been unexpectedly discovered that unlike azithromycin, triazole-containing macrolides described herein have an optimal half-life in the pharynx and lungs, which allows for efficacy in treating disease in the lungs with a lower potential for resistance development. It has also been surprisingly discovered that the triazole-containing macrolides described herein may be administered by inhalation, including intranasal and oral inhalation, and other nasal, sinus, respiratory tract, pulmonary, and intrabronchial routes. It has also been unexpectedly discovered that the triazole-containing macrolides described herein exhibit a large volume of distribution.
It has also been discovered that the macrolides described herein are useful in treating respiratory tract infections (RTIs). It has been surprisingly discovered that the compounds described herein also achieve sufficiently high lung levels upon oral administration. Accordingly, methods are described herein for the treatment and/or prophylaxis of acute and chronic pulmonary and endobronchial diseases, where the methods include the step of administering or co-administering one or more macrolides described herein to a host animal. The macrolides may be administered by a variety of routes, including but not limited to oral, parenteral, inhalation, and like routes of administration. Without being bound by theory, it is believed herein that the utility of the macrolides described herein is due at least in part to the unexpectedly high lung tissue levels of the compounds following administration, including oral and parenteral administration. It has also been surprisingly discovered that the compounds do not have to be administered by inhalation to achieve efficacious lung levels.
It has also been discovered that the macrolide compounds described herein are useful in the treatment and/or prophylaxis of acute and chronic pulmonary and endobronchial diseases, such as diseases caused by or exacerbated by bacteria, including Pseudomonas aeruginosa seen in CF patients, chronic bronchitis, and bronchiectasis. It has been discovered that the macrolides described herein have potent anti-inflammatory activities, and therefore are useful in treating the inflammatory component of various pulmonary and endobronchial diseases, such as CF.
It has also been discovered that the macrolides described herein may be co-administered with other antibiotics, such as aminoglycosides, fluoroquinolones, aztreonam, fosfomycin, and the like, and that such co-administration give unexpectedly high efficacy. Without being bound by theory, it is believed herein that the unexpectedly high efficacy may be due to one or more properties of the macrolides. One such property may be that the macrolides have been shown to not antagonize the activity of other antibiotics, such as aminoglycoside antibiotics, which has been reported for other antibacterial agents during co-administration. Another such property may be that the macrolides surprisingly synergize the activity of other antibiotics, such as aminoglycoside antibiotics.
It has also been discovered that the macrolides described herein are useful in treating diseases that are caused at least in part by Escherichia coli, Enterobacteria species, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, multidrug resistant Pseudomonas aeruginosa. The macrolides may be administered alone or in combination with other antibiotics, such as aminoglycosides, fluoroquinolones, aztreonam, fosfomycin, and the like.
Described herein are compounds, compositions, formulations, uses in the manufacture of medicaments, and methods for treating respiratory infections, and related diseases, including cystic fibrosis (CF), diseases caused at least in part by Mycobacterium avium complex (MAC) or Mycobacterium hominus (MAH), patients suffering from infection co-morbid with HIV, AIDS and/or AIDS related diseases, and other immunocompromised patients suffering from infection. Without being bound by theory, it is believed herein that efficacy in treating disease such as CF is due at least in part to the combination of antibacterial and anti-inflammatory activity of the compounds administered.